Dear Carlos,
Thanks for suggesting Dan Roe's protocol. I will try that. But, for now I
equilibrated the dark state system (2v1a) exactly as per the method
described in your paper. What I find is, water and ions still move a quite
away from the protein during equilibration and the overall system has
expanded a lot in volume. Although the production MD seems to be going
fine, the issue now is that a 4ns simulation ( nstlim = 1000000, dt =
0.004) is running for about 20 mins on the GPU. Whereas, the light state
system with the same size (2v1b, in which the system didn't expand much
during equilibration) took only 2 mins for a 4ns production run.
Kindly let me know if this expansion (and the corresponding slow down) is a
usual thing to happen with the dark system. If not, can you please suggest
what measures I might have missed which make my run slower.
Thanks,
Amit
On Wed, Nov 25, 2020 at 8:50 PM Carlos Simmerling <
carlos.simmerling.gmail.com> wrote:
> agreed - this the one I meant earlier in the thread when I said " Dan Roe
> also has a nice paper on equilibration"
>
> On Wed, Nov 25, 2020 at 10:12 AM Daniel Roe <daniel.r.roe.gmail.com>
> wrote:
>
> > Hi,
> >
> > You may also want to try the system preparation protocol outlined
> > here: https://aip.scitation.org/doi/abs/10.1063/5.0013849
> >
> > -Dan
> >
> > On Tue, Nov 24, 2020 at 7:41 AM Carlos Simmerling
> > <carlos.simmerling.gmail.com> wrote:
> > >
> > > it's quite different equilibration from what we used. I don't know if
> the
> > > problems you are seeing are due to that, but since the 2v1b works and
> > 2v1a
> > > does not, it suggests that it might be due to equilibration. When using
> > > 2v1a as the initial structure, you are far from equilibrium at the
> start
> > > and need to slowly adjust to introducing the new bond and adjusting to
> > new
> > > geometries in the flavin, etc. In my experience the GPU code can run
> into
> > > trouble if the system is at all unstable. You might try tracking your
> > > energies and other properties from the mdout files and see if they have
> > > reached a plateau before going to the next step, your MD stages are
> > fairly
> > > short.
> > > Here is what we used that worked well for us:
> > >
> > > Minimization and equilibration were carried out using Amber version
> > > 16.(39,40) Initial minimization was performed for 100 000 steps with
> > > restraints on all atoms except hydrogens, water, C450, and the flavin.
> > The
> > > restraint force constant was 100 kcal·mol–1·Å–2. Next, the system was
> > > heated from 100 to 298 K over 1 ns in the NVT ensemble, with a time
> step
> > of
> > > 1 fs and SHAKE on all bonds including hydrogen. A nonbonded cutoff of
> 8 Å
> > > was used, with long-range electrostatics included by the particle mesh
> > > Ewald method.(41) The same restraints were maintained. Temperature was
> > > maintained using a Langevin thermostat with γ set to 1.0. Next,
> pressure
> > > and density were relaxed using 1 ns NPT simulation at 298 K with a
> strong
> > > pressure coupling constant of 0.1 and all other parameters maintained
> > from
> > > the prior step. Next, 1 ns MD was performed using the same protocol but
> > > with restraint force constant reduced to 10.0 and pressure coupling
> > > constant increased to 0.5. Next, minimization was performed for 10000
> > steps
> > > after removing all restraints except those on protein backbone CA, N,
> > and C
> > > atoms, and no restraints on C450. Next, 1 ns MD in the NPT ensemble at
> > 298
> > > K was performed using the same protocol as above, with restraints only
> on
> > > backbone CA, N, and C atoms excepting C450. The restraint force
> constant
> > > was then reduced from 10.0 to 1.0 and an additional 1 ns MD was carried
> > > out, followed by 1 ns MD with restraint force constant reduced to 0.1.
> > > Finally, 1 ns of fully unrestrained MD was performed with NPT at 298 K.
> > >
> > > On Tue, Nov 24, 2020 at 6:44 AM Amit Sharma (Asstt. Prof., MCARS) <
> > > asharma4.jmi.ac.in> wrote:
> > >
> > > > I tried simulation using 2v1b (crystal structure in photoexcited
> > state). It
> > > > works fine in that case and is currently running at 2 micro second.
> > > >
> > > > My equilibration protocol is as follows
> > > >
> > > > 1. 3000 cycle minimization under 100 kcal mol-1 A-2 restraint on the
> > > > protein
> > > > 2. 5000 cycle minimization under 25 kcal mol-1 A-2 restraint on the
> > protein
> > > > 3. 100000 cycle minimization without any restraints
> > > > 4. 20ps md at nvt where system was heated from 0 to 300K, with 10
> kcal
> > > > mol-1 A-2 restraint on the protein, 2fs time step by keeping SHAKE
> on.
> > cut
> > > > of 10 A
> > > > 5. 80ps md at nvt at 300 K, with 0.5 kcal mol-1 A-2 restraint on the
> > > > protein, 2fs time step by keeping SHAKE on. cut of 10 A
> > > >
> > > > System remains fine until step 5, but blows when I start (using gpu)
> > ntp
> > > > (ntb = 2, pressure 1atm, ntp = 1) at 300K.
> > > >
> > > >
> > > > When doing the same using cpu, it seems fine at least for initial
> > 100ps.
> > > > But, issue is that I cannot go on cpu for the simulation where a few
> > micro
> > > > second run is needed before we could actually see J alpha unfolding.
> > > >
> > > > In your paper you retain the crystallographic water and use four
> point
> > opc
> > > > water. But, what I am using is tip3p. Can that make a difference?
> > > >
> > > > Amit
> > > >
> > > >
> > > > On Tue, Nov 24, 2020 at 4:40 PM Carlos Simmerling <
> > > > carlos.simmerling.gmail.com> wrote:
> > > >
> > > > > Have you tried the simulation without adding the adduct? Also you
> > didn't
> > > > > describe your equilibration protocol. I believe the one we used
> > should be
> > > > > described in our paper on that system. Dan Roe also has a nice
> paper
> > on
> > > > > equilibration.
> > > > > Carlos
> > > > >
> > > > > On Tue, Nov 24, 2020, 6:05 AM Amit Sharma (Asstt. Prof., MCARS) <
> > > > > asharma4.jmi.ac.in> wrote:
> > > > >
> > > > > > Hi,
> > > > > >
> > > > > > I trying to simulate protein having of FMN Cys adduct.
> > > > > >
> > > > > > When running md using nvt and positional restraints of 0.5 kcal
> > mol-1
> > > > A-2
> > > > > > on the protein, the system remains fine.
> > > > > >
> > > > > > But as I switch to npt and remove all the restraints system blows
> > up
> > > > and
> > > > > > water molecules start flying away.
> > > > > >
> > > > > > Error message is as follows:
> > > > > >
> > > > > > "ERROR: Calculation halted. Periodic box dimensions have changed
> > too
> > > > > much
> > > > > > from their initial values.
> > > > > > Your system density has likely changed by a large amount,
> > probably
> > > > from
> > > > > > starting the simulation from a structure a long way from
> > equilibrium.
> > > > > >
> > > > > > [Although this error can also occur if the simulation has blown
> > up
> > > > for
> > > > > > some reason]
> > > > > >
> > > > > > The GPU code does not automatically reorganize grid cells and
> > thus
> > > > you
> > > > > > will need to restart the calculation from the previous restart
> > file.
> > > > > > This will generate new grid cells and allow the calculation to
> > > > > continue.
> > > > > > It may be necessary to repeat this restarting multiple times if
> > your
> > > > > > system
> > > > > > is a long way from an equilibrated density.
> > > > > >
> > > > > > Alternatively you can run with the CPU code until the density
> has
> > > > > > converged
> > > > > > and then switch back to the GPU code."
> > > > > >
> > > > > > Can anyone suggest how to deal with this?
> > > > > >
> > > > > > Thank You,
> > > > > >
> > > > > > Amit
> > > > > >
> > > > > > --
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